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Regulation of 2-oxoglutarate (alpha-ketoglutarate) dehydrogenase stability by the RING finger ubiquitin ligase Siah.

http://www.ncbi.nlm.nih.gov/pubmed/15466852

The 2-oxoglutarate dehydrogenase complex (OGHDC) (also known as the alpha-ketoglutarate dehydrogenase complex) is a rate-limiting enzyme in the mitochondrial Krebs cycle. Here we report that the RING finger ubiquitin-protein isopeptide ligase Siah2 binds to and targets OGDHC-E2 for ubiquitination-dependent degradation. OGDHC-E2 expression and activity are elevated in Siah2(-/-) cells compared with Siah2(+)(/)(+) cells. Deletion of the mitochondrial targeting sequence of OGDHC-E2 results in its cytoplasmic localization and rapid proteasome-dependent degradation in Siah2(+)(/)(+) but not in Siah2(-/-) cells. Significantly, because of its overexpression or disruption of the mitochondrial membrane potential, the release of OGDHC-E2 from mitochondria to the cytoplasm also results in its concomitant degradation. The role of the Siah family of ligases in the regulation of OGDHC-E2 stability is expected to take place under pathological conditions in which the levels of OGDHC-E2 are altered.

Pubmed ID: 15466852 RIS Download

Mesh terms: Animals | Blotting, Western | Cell Line | Cytoplasm | Electrophoresis, Polyacrylamide Gel | HeLa Cells | Humans | Immunoprecipitation | Ketoglutarate Dehydrogenase Complex | Kinetics | Membrane Potentials | Mice | Microscopy, Fluorescence | Mitochondria | Nuclear Proteins | Plasmids | Proteasome Endopeptidase Complex | Protein Binding | Protein Structure, Tertiary | Transcription Factors | Transfection | Transgenes | Ubiquitin | Ubiquitin-Protein Ligases

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Associated grants

  • Agency: NCI NIH HHS, Id: CA78419

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